Featured ArticlesVolume 3 | No. 7 | October 2014
|Leptin receptor neurons neurons regulate body weight independent of food intakeThe data of Rezai-Zadeh and colleagues indicate that leptin receptors in the dorsomedial hypothalamus induce energy expenditure via brown adipose tissue thermogenesis and locomotor activity with similar magnitudes and chronology, suggesting that both thermogenic mechanisms are initiated by the activation DMH/DHA LepRb neurons.|
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Leptin responsive neurons are important to control energy homeostasis. We previously identified leptin receptor (LepRb) expressing neurons within the dorsomedial hypothalamus/dorsal hypothalamic area (DMH/DHA) which are related to neuronal circuits that control brown adipose tissue (BAT) thermogenesis. Intra-DMH leptin injections also activate sympathetic outflow to BAT, but whether this requires direct action of DMH/DHA LepRb neurons and whether this is physiologically relevant for energy expenditure (EE) and body weight regulation remains to be determined. We show that pharmacogenetic activation of DMH/DHA LepRb neurons promotes BAT thermogenesis, locomotor activity, EE and decreases body weight. Similarly, intra-DMH/DHA leptin injections normalized hypothermia and attenuated body weight gain in leptin-deficient ob/ob mice. Conversely, LepRb ablation from DMH/DHA neurons remarkably drives weight gain, reduces EE and locomotor activity. Observed body weight changes were largely independent of food intake. Our data highlight DMH/DHA LepRb neurons as sufficient and necessary to regulate EE and body weight. [Hide abstract]
|AgRP neurons control meal patternThe results of Tan and colleagues confirm a key role for AgRP/NPY neurons in the response to restricted feeding suggesting that it is a key neural component of the food entrainable oscillator.|
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While the SCN controls the circadian clock, further evidence suggests the existence of a food-entrainable oscillator (FEO) that links behavior to changes in food availability such as during restricted feeding (RF). We found that the activity of AgRP/NPY neurons changed rhythmically during RF suggesting that these neurons are a component of the FEO. We next ablated AgRP/NPY neurons in neonates with diphtheria toxin resulting in the loss of ∼50% of AgRP/NPY neurons. Body weight and food intake were unchanged in adult animals after neonatal ablation, as were the responses to leptin treatment, leptin withdrawal, food deprivation and ghrelin treatment. However, ablated animals showed 30% mortality within 4 days of RF. Moreover, the recovery of body weight and food intake in surviving animals lagged behind controls with an absence of food anticipatory activity even after three days. These findings identify AgRP/NPY neurons as a key cellular component of the food-entrained oscillator. [Hide abstract]
|CB1 receptors regulate adiposity and glucose metabolismThe data of Cardinal and colleagues demonstrate that CB1 receptors in the hypothalamic ventromedial nucleus (VMN) determine metabolic and molecular adaptations to different environmental dietary conditions. In order to do so, CB1 receptors in VMN neurons orchestrate peripheral use of substrates and fine-tune sensitivity (or resistance) to the actions of leptin.|
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Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB1) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change. [Hide abstract]
|Regulation of ghrelin secretion in the contexts of obesity and weight lossIn the present study, Uchida and colleagues tested the hypothesis that circulating ghrelin levels are altered in obesity and after weight loss by Roux-en-Y gastric bypass through changes in ghrelin cell responsiveness to physiological cues.|
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The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion – glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss. [Hide abstract]
|Fractalkine protects beta-cells against TNFαIn this study, Rutti and colleagues provide evidence that fractalkine (CX3CL1) is a protective factor against the adverse effects of TNFα on beta-cells. CX3CL1 impacts human islets by decreasing glucagon secretion but not insulin and it decreases basal apoptosis of human beta-cells.|
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We have previously shown the existence of a muscle-pancreas intercommunication axis in which CX3CL1 (fractalkine), a CX3C chemokine produced by skeletal muscle cells, could be implicated. It has recently been shown that the fractalkine system modulates murine β-cell function. However, the impact of CX3CL1 on human islet cells especially regarding a protective role against cytokine-induced apoptosis remains to be investigated.
Gene expression was determined using RNA sequencing in human islets, sorted β - and non β -cells. Glucose-stimulated insulin secretion (GSIS) and glucagon secretion from human islets was measured following 24 h exposure to 1-50 ng/ml CX3CL1. GSIS and specific protein phosphorylation were measured in rat sorted β-cells exposed to CX3CL1 for 48 h alone or in the presence of TNFα (20ng/ml). Rat and human β-cell apoptosis (TUNEL) and rat β-cell proliferation (BrdU incorporation) were assessed after 24 h treatment with increasing concentrations of CX3CL1.
Both CX3CL1 and its receptor CX3CR1 are expressed in human islets. However, CX3CL1 is more expressed in non- β cells than in β-cells while its receptor is more expressed in β-cells. CX3CL1 decreased human (but not rat) β-cell apoptosis. CX3CL1 inhibited human islet glucagon secretion stimulated by low glucose but did not impact human islet and rat sorted β-cell GSIS. However, CX3CL1 completely prevented the adverse effect of TNFα on GSIS and on molecular mechanisms involved in insulin granule trafficking by restoring the phosphorylation (Akt, AS160, paxillin) and expression (IRS2, ICAM-1, Sorcin, PCSK1) of key proteins involved in these processes.
We demonstrate for the first time that human islets express and secrete CX3CL1 and CX3CL1 impacts them by decreasing glucagon secretion without affecting insulin secretion. Moreover, CX3CL1 decreases basal apoptosis of human β-cells. We further demonstrate that CX3CL1 protects β-cells from the adverse effects of TNFα on their function by restoring the expression and phosphorylation of key proteins of the insulin secretion pathway [Hide abstract]
Ca2+ release is not necessary to increase glucose transportIn this study, Jensen and colleagues provide evidence that combined AMPK activation and mechanical stress can fully account for the contraction-stimulated glucose transport-response ex vivo, strongly suggesting that AMPK and stretch-activated signalling, but not sarcoplasmatic reticulum Ca2+ per se, regulates glucose transport during skeletal muscle contraction.|
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Understanding how muscle contraction orchestrates insulin-independent muscle glucose transport may enable development of hyperglycemia-treating drugs. The prevailing concept implicates Ca2+ as a key feed forward regulator of glucose transport with secondary fine-tuning by metabolic feedback signals through proteins such as AMPK. Here, we demonstrate in incubated mouse muscle that Ca2+ release is neither sufficient nor strictly necessary to increase glucose transport. Rather, the glucose transport response is associated with metabolic feedback signals through AMPK, and mechanical stress-activated signals. Furthermore, artificial stimulation of AMPK combined with passive stretch of muscle is additive and sufficient to elicit the full contraction glucose transport response. These results suggest that ATP-turnover and mechanical stress feedback are sufficient to fully increase glucose transport during muscle contraction, and call for a major reconsideration of the established Ca2+ centric paradigm. [Hide abstract]
|Myocardial ketone oxidation is cardioprotectiveThe data of Schugar and colleagues demonstrate that myocardial ketone oxidation is cardioprotective in sepsis and pressure overload, it regulates myocardial protein acetylation and attenuates stress-induced ROS accumulation.|
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Exploitation of protective metabolic pathways within injured myocardium still remains an unclarified therapeutic target in heart disease. Moreover, while the roles of altered fatty acid and glucose metabolism in the failing heart have been explored, the influence of highly dynamic and nutritionally-modifiable ketone body metabolism in the regulation of myocardial substrate utilization, mitochondrial bioenergetics, reactive oxygen species (ROS) generation, and hemodynamic response to injury remains undefined.
Here we use mice that lack the enzyme required for terminal oxidation of ketone bodies, succinyl-CoA:3-oxoacid CoA transferase (SCOT) to determine the role of ketone body oxidation in the myocardial injury response. Tracer delivery in ex vivo perfused hearts coupled to NMR spectroscopy, in vivo high-resolution echocardiographic quantification of cardiac hemodynamics in nutritionally and surgically-modified mice, and cellular and molecular measurements of energetic and oxidative stress responses are performed.
While germline SCOT-knockout (KO) mice die in the early postnatal period, adult mice with cardiomyocyte-specific loss of SCOT (SCOT-Heart-KO) remarkably exhibit no overt metabolic abnormalities, and no differences in left ventricular mass or impairments of systolic function during periods of ketosis, including fasting and adherence to a ketogenic diet. Myocardial fatty acid oxidation is increased when ketones are delivered but cannot be oxidized. To determine the role of ketone body oxidation in the remodeling ventricle, we induced pressure overload injury by performing transverse aortic constriction (TAC) surgery in SCOT-Heart-KO and αMHC-Cre control mice. While TAC increased left ventricular mass equally in both groups, at four weeks post-TAC, myocardial ROS abundance was increased in myocardium of SCOT-Heart-KO mice, and mitochondria and myofilaments were ultrastructurally disordered. Eight weeks post-TAC, left ventricular volume was markedly increased and ejection fraction was decreased in SCOT-Heart-KO mice, while these parameters remained normal in hearts of control animals.
These studies demonstrate the ability of myocardial ketone metabolism to coordinate the myocardial response to pressure overload, and suggest that the oxidation of ketone bodies may be an important contributor to free radical homeostasis and hemodynamic preservation in the injured heart. [Hide abstract]
|Foxo1 regulates the activity of the sympathetic nervousThe results of Kajimura and colleagues demonstrate that the transcription factor FoxO1 is expressed in neurons of the locus coeruleus and that it favors Dbh expression and catecholamine synthesis. As a result, FoxO1 regulates physiological processes such as energy expenditure, glucose metabolism, and bone mass accrual that are under the influence of the sympathetic nervous system.|
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The transcription factor FoxO1 regulates multiple physiological processes. Here, we show that FoxO1 is highly expressed in neurons of the locus coeruleus and of various sympathetic ganglions, but not in the adrenal medulla. Consistent with this pattern of expression, mice lacking FoxO1 only in sympathetic neurons (FoxO1Dbh−/−) display a low sympathetic tone without modification of the catecholamine content in the adrenal medulla. As a result, FoxO1Dbh−/− mice demonstrate an increased insulin secretion, improved glucose tolerance, low energy expenditure, and high bone mass. FoxO1 favors catecholamine synthesis because it is a potent regulator of the expression of Dbh that encodes the initial and rate-limiting enzyme in the synthesis of these neurotransmitters. By identifying FoxO1 as a transcriptional regulator of the sympathetic tone, these results advance our understanding of the control of some aspects of metabolism and of bone mass accrual. [Hide abstract]